Throughout this application, various publications, patents, and published patent applications are referred to by an identifying citation; full citations for these documents may be found at the end of the specification immediately preceding the claims. The disclosures of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
The most important method used for the commercial preparation of acylaromatic compounds is Friedel-Crafts aromatic acylation. In the typical Friedel-Crafts aromatic acylation, a Lewis acid reagent, such as aluminum trichloride (AlCl.sub.3) is added to a mixture of an acyl chloride and an aromatic compound to cause a vigorous reaction that, after hydrolytic quenching, generates the acylaromatic. ##STR1## The reaction is usually conducted in an inert solvent such as chlorinated solvents, like dichloromethane, and deactivated aromatics, typically nitrobenzene. A little more than a molar equivalent of the Lewis acid reagent is required, since the ketone product forms a strong Lewis acid-base complex with the reagent. The addition of water and acid to the reaction mixture after the reaction destroys this complex and liberates the ketone. Such Friedel-Crafts aromatic acylation reactions are often highly efficient and selective reactions and are commonly used despite their substantial undesirable features.
Aluminum chloride, the most effective and commonly used Lewis Acid reagent for this reaction, is an unpleasant, hazardous material to handle. Large quantities of aluminum chloride, at least stoichiometric, are usually needed for the acylation. In some acylation reactions two or three times the stoichiometric amount of aluminum chloride has to be used.
Aluminum chloride is in general not recovered for reuse. At completion, the reaction is quenched with a considerable volume of water. This requires the use of a much larger reactor, to accommodate the quench volume, or the use of a second reactor 1.5-2 times larger than the first. There is a considerable negative impact associated with the tying up of equipment and lengthening of the reaction cycles resulting from this quench step. Also considerable cooling is required during the quench process. Disposal of the considerable aqueous aluminum waste products can be a problem for companies involved in the Friedel-Crafts on only an occasional basis.
The conventional Friedel-Crafts aromatic acylation typically utilizes an acyl halide reactant, usually an acyl chloride. This must be first prepared from the carboxylic acid, typically using a reagent like thionyl chloride that is not a particularly desirable compound to handle on large scale. Hydrogen chloride gas, is released in the formation of formation of the acyl chloride (along with SO.sub.2 when using thionyl chloride) and in the acylation reaction, and must be abated with an acid gas scrubber.
Also, the solvent of choice for many such conventional Friedel-Crafts acylation processes is a chlorinated hydrocarbon, such as dichloromethane, whose use in industrial synthesis has become increasingly less acceptable.
Intramolecular Friedel-Crafts acylation may also be used to effect ring closure of arylalkanoic acids and their acyl halide derivatives. When the acyl reactant is an acyl halide, the reagent is typically a Lewis acid such as AlCl.sub.3 or ZnBr.sub.2. When the acyl reactant is a carboxylic acid, the reagent is typically a protic acid, such as hydrogen fluoride, methanesulfonic acid, or polyphosphoric acid (Yamoto et al., 1991). A 1:10 by weight solution of phosphorus pentoxide in methanesulfonic acid has been examined as an alternative to polyphosphoric acid in similar acylation reactions (Eaton et al., 1973).
Many heterocyclic aromatic systems, including firans, thiophenes, pyrans, and pyrroles can be acylated in. good yield by Friedel-Crafts acylation.
Reagents other than acid chlorides, such as carboxylic acids, anhydrides, and ketenes have also been used successfully. With active substrates, such as aryl ethers, the reaction can sometimes be carried out with catalytic amounts of the reagent. Typically, the catalyst is a Lewis acid, such as AlCl.sub.3, BF.sub.3, FeCl.sub.3 and ZnCl.sub.2, but other catalysts, including protic acids have been used.
The estrogen modulator drugs known as tamoxifen (1,2-diphenyl-1-4-2-(N,N,-dimethylamino) ethoxy!phenyl!-1-butene) and droloxifene (3--1-4-2-(N,N,-dimethylamino) ethoxy!phenyl!-2-phenyl-1-butenyl!phenol) are typically prepared via a versatile acylaromatic intermediate 1-4-2-(N,N-dimethyl-amino) ethoxy!phenyl!-2-phenyl-1-butanone (see Tiovola et al., 1996). ##STR2## This acylaromatic intermediate is typically prepared by a conventional Friedel-Crafts acylation reaction. The conventional synthetic pathway is shown below. Greater than two mole equivalents of AlCl.sub.3 are required as the amine function complexes with one equivalent and the ketone group of the product complexes with a second equivalent. ##STR3##
Recently, alternative synthetic routes to this acylaromatic have been investigated to avoid the disadvantages of the conventional Friedel-Crafts acylation reaction. Some have adapted the use of anhydrides, specifically trifluoroacetic acid anhydride, in acylation reactions (see Gaili, 1979).
In one method (Smyth et al., 1997), N,N-dimethyl-2-phenoxyethylamine and 2-phenylbutyric acid are the starting materials, and the reaction involves in situ formation of the trifluoroacetyl mixed anhydride, as shown below. ##STR4## Here, excess trifluoroacetic acid anhydride (TFAA) is added to one equivalent of 2-phenylbutyric acid to form the mixed anhydride and trifluoroacetic acid (TFA). One equivalent of N,N-dimethyl-2-phenoxyethylamine is then added, followed by one equivalent of 85% phosphoric acid. The mixture is then refluxed to yield the desired ketone.
In another method (McCague, 1985), the trifluoroacetyl mixed anhydride is reacted, instead, with 2-phenoxyethyl chloride, and the product is next reacted with dimethylamine to yield the desired ketone, as shown below: ##STR5##
These processes using trifluoroacetic anhydride are not economically attractive relative to conventional Friedel-Crafts acylation due to the expense of trifluoroacetic anhydride. Recognizing this, Smyth et al. proposed to recycle the trifluoroacetic acid produced in the process by distillation from the acylation reaction mixture, reaction with 4+equivalents of phosphorus pentoxide to reform trifluoroacetic anhydride, and recovery of the trifluoroacetic anhydride by distillation . While this may improve the economics of the processes based on trifluoroacetic anhydride, it is none the less still a costly and undesirable operation.